Assembling a primary cilium

Kim, Sehyun; Dynlacht, Brian David

doi:10.1016/j.ceb.2013.04.011

Cited by 139 publications

(127 citation statements)

References 66 publications

(92 reference statements)

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“…Primary cilia are composed of a '9 þ 0' microtubule-based axoneme, which is in turn derived from and anchored to the cell via the basal body (5). In photoreceptors, the sensory cilium forms a narrow isthmus that connects the metabolically active inner segment (IS) to the outer segment (OS).…”

Section: Introductionmentioning

confidence: 99%

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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Ciliary defects can result in severe disorders called ciliopathies. Mutations in NPHP5 cause a ciliopathy characterized by severe childhood onset retinal blindness, Leber congenital amaurosis (LCA), and renal disease. Using the canine NPHP5-LCA model we compared human and canine retinal phenotypes, and examined the early stages of photoreceptor development and degeneration, the kinetics of photoreceptor loss, the progression of degeneration and the expression profiles of selected genes. NPHP5-mutant dogs recapitulate the human phenotype of very early loss of rods, and relative retention of the central retinal cone photoreceptors that lack function. In mutant dogs, rod and cone photoreceptors have a sensory cilium, but develop and function abnormally and then rapidly degenerate; L/M cones are more severely affected than S-cones. The lack of outer segments in mutant cones indicates a ciliary dysfunction. Genes expressed in mutant rod or both rod and cone photoreceptors show significant downregulation, while those expressed only in cones are unchanged. Many genes in celldeath and -survival pathways also are downregulated. The canine disease is a non-syndromic LCA-ciliopathy, with normal renal structures and no CNS abnormalities. Our results identify the critical time points in the pathogenesis of the photoreceptor disease, and bring us closer to defining a potential time window for testing novel therapies for translation to patients. †

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Section: Introductionmentioning

confidence: 99%

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

et al. 2016

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“…In vertebrates, cilia are classified as motile or nonmotile (primary). Motile cilia often occur in epithelial tissues to generate fluid flow, while non-motile cilia are distributed widely and are considered critical for extracellular signal reception and transduction [1,2]. Cilia play essential roles in vertebrate development, including establishment of left-right asymmetry, and brain and kidney development [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

NudC regulates actin dynamics and ciliogenesis by stabilizing cofilin 1

Zhang

et al. 2015

Cell Res

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Emerging data indicate that actin dynamics is associated with ciliogenesis. However, the underlying mechanism remains unclear. Here we find that nuclear distribution gene C (NudC), an Hsp90 co-chaperone, is required for actin organization and dynamics. Depletion of NudC promotes cilia elongation and increases the percentage of ciliated cells. Further results show that NudC binds to and stabilizes cofilin 1, a key regulator of actin dynamics. Knockdown of cofilin 1 also facilitates ciliogenesis. Moreover, depletion of either NudC or cofilin 1 causes similar ciliary defects in zebrafish, including curved body, pericardial edema and defective left-right asymmetry. Ectopic expression of cofilin 1 significantly reverses the phenotypes induced by NudC depletion in both cultured cells and zebrafish. Thus, our data suggest that NudC regulates actin cytoskeleton and ciliogenesis by stabilizing cofilin 1.

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“…Its assembly and maintenance require the intraflagellar transport that is driven by kinesin-2 motor (22). The motor transports proteins toward the "plus" end of microtubule and is comprised of two motor subunits, KIF3A and KIF3B, and an associated protein, KAP3 (23,24).…”

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confidence: 99%

Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia

Zhong

Zhao

Yuan

et al. 2016

Journal of Biological Chemistry

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Folliculin (FLCN) is the tumor suppressor associated withBirt-Hogg-Dubé (BHD) syndrome that predisposes patients to incident of hamartomas and cysts in multiple organs. Its inactivation causes deregulation in the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway. However, the underlying mechanism is poorly defined. In this study, we show that FLCN is a ciliary protein that functions through primary cilia to regulate mTORC1. In response to flow stress, FLCN associates with LKB1 and recruits the kinase to primary cilia for activation of AMPK resided at basal bodies, which causes mTORC1 down-regulation. In cells depleted of FLCN, LKB1 fails to accumulate in primary cilia and AMPK at the basal bodies remains inactive, thus nullifying the inhibitory effect of flow stress on mTORC1 activity. Our results demonstrate that FLCN is part of a flow sensory mechanism that regulates mTORC1 through primary cilia. Birt-Hogg-Dubé (BHD)4 syndrome is a rare autosomal dominant genetic disorder characterized by development of hamartomas and cysts in multiple organs, including skin, lung, colon, and kidney (1, 2). The syndrome is caused by germ-line mutations in the BHD gene, which encodes the folliculin protein (FLCN), a 64-kDa polypeptide that shares little sequence similarity with any other known proteins (3). FLCN is found to complex with AMPK and FNIP1, although the significance of the complex for FLCN function remains unclear (4). In mouse models FLCN deficiency leads to development of polycystic kidneys and renal cell carcinoma that are characteristically similar to those found in BHD patients (5, 6). Inactivation of FNIP1, together with its homolog FNIP2, in mice also produces similar phenotypes as does by FLCN deficiency (7), suggesting that FNIP1 may be required for FLCN function. Analyses of tumors derived from BHD patients and FLCN deficient animals have revealed deregulation in mammalian target of rapamycin complex 1 (mTORC1) signaling, a key event in tumorigenesis (5, 8 -12). This abnormality in mTORC1 signaling is believed to be a major contributor to the pathological conditions in BHD, as inhibition of mTORC1 with rapamycin has been found to reduce the BHD tumor growth in animal models (5, 6). However, the mechanism by which FLCN regulates mTORC1 remains poorly understood.At non-cycling resting state, most eukaryotic cells possess a microtubule-based membranous protrusion from cell surface termed as primary cilium (13). This unique structure plays a critical role in maintaining tissue homeostasis by functioning as a sensor for extracellular fluidic shear stress and chemicals (14, 15). Many signaling pathways involved in cell growth and proliferation are regulated by this environmental sensor, among which is the mTORC1 pathway (16 -18). Several upstream regulators of mTORC1 have been found to localize to primary cilia, including the tuberous sclerosis complex proteins, LKB1 and AMPK (19 -21). A recent study has shown that primary cilia are able to act through a LKB1-and AMPK-dependent mechanism to dow...

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Assembling a primary cilium

Cited by 139 publications

References 66 publications

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

Overlap of abnormal photoreceptor development and progressive degeneration in Leber congenital amaurosis caused byNPHP5mutation

NudC regulates actin dynamics and ciliogenesis by stabilizing cofilin 1

Tumor Suppressor Folliculin Regulates mTORC1 through Primary Cilia

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